Preparing process for Eptifibatide

Abstract

The present invention relates to the preparation of cyclic peptide, and is especially new Fmoc-solid phase process of preparing Eptifibatide. The new process is superior to liquid phase process, which has long synthesis period, and BOC solid phase process, which uses virulent and corrosive material. The technological scheme is that the Eptifibatide preparing process includes the following steps: eliminating Fmoc protection of Fmoc-Rink Amide AM resin to obtain H2N-Rink Amide AM resin; connecting various protective amino acids successively to obtain corresponding resin; eliminating Fmoc-protection radical and Kaiser test to detect reaction procedure; preparing S-triphenyl mercapto propionyl-N, N-ditert butyl oxycarbonyl-homoarginine with lysine; grafting S-triphenyl mercapto propionyl-N, N-ditert butyl oxycarbonyl-homoarginine; eliminating side chain protecting radical and resin to reduce into coarse product; and cyclization, oxidation, HPLC tracking purification to obtain pure product.

Description

1. Technical field [0001] The invention relates to a preparation process of cyclic peptides, in particular to a new process for preparing Efibuta by using the Fmoc-strategy solid-phase method. 2. Background technology [0002] Epifibatide is a cyclic peptide containing mercaptopropionyl and six amino acid residues, and it is the main active ingredient of the cardiovascular drug Intergrelin. Molecular formula: C 35 h 49 N 11 o 9 S 2 . At present, the manufacturer of this product in the world is Bachem Company in Switzerland. The two lines they use are: liquid phase method and Boc-strategy solid phase method. The preparation process of the liquid phase method includes: 1. The product Boc-Lys(Tfa)-Gly-OMe obtained by condensation of Gly-OMe and Boc-Lys(Tfa)-OH reacts with Mpa(Trt)-ONSu to obtain the product Mpa(Trt)- Lys(Tfa)-Gly-OMe, guanidinylation, saponification, to get Mpa(Trt)-Har-Gly-OH (fragment 1); 2, Z-Asp(OtBu)-OH and Trp-Pro-OMe condensation reaction, Obtain...

AI Technical Summary

Problems solved by technology

The BOC strategy solid-phase method also has two disadvantages: 1. In the process of converting arginine into homoarginine, it is carried out under heterogeneous conditions, and the reaction is not easy to complete

And whether this degree of conversion is completely impossible to detect and track on the resin, thus affecting the purity of the crude product, resulting in increased difficulty in purification and reduced yield

2. When the polypeptide is washed off from the resin, highly corrosive and highly toxic hydrogen fluoride is used, which is easy to cause environmental pollution and cause a series of environmental and social problems

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